Quaternary phosphonium coated surfaces and methods of making the same

ABSTRACT

Disclosed herein is a composition comprising a substrate with functionalized surface covalently bound to an anti-infective agent, such as a quaternary phosphonium compound with anti-bacterial activity against a broad range of bacteria, methods of synthesizing an anti-infective composition, and its resultant antimicrobial performance.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/068,347, filed Oct. 24, 2014, the entirety ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to surface attachment of quaternaryphosphonium compounds with anti-bacterial activity against a broad rangeof bacteria. In particular, methods are provided for attaching varioussubstrate surfaces to quaternary phosphonium compounds to obtainanti-bacterial activity.

BACKGROUND OF THE INVENTION

The need for control of infection is a vital concern for many, frompublic health officials, hospital and school administrators and thelike, to private citizens. Typically, control of infection can beachieved by the topical application of disinfectants, antiseptics,antibacterials and the like to surfaces likely to be contacted byinfectious agents. Common disinfectants include active chlorine such ashypochlorites, chloramines, dichloroisocyanurate andtrichloroisocyanurate, wet chlorine, chlorine dioxide and the like,active oxygen, including peroxides, such as peracetic acid, potassiumpersulfate, sodium perborate, sodium percarbonate and urea perhydrate,iodine compounds such as povidone iodide, iodine tincture, iodinatednonionic surfactants, concentrated alcohols such as ethanol, n-propanoland isopropanol and mixtures thereof; 2-phenoxyethanol and 1- and2-phenoxypropanols, phenolic compounds, cresols, halogenated phenols,such as hexachlorophene, triclosan, trichlorophenol, tribromophenol,pentachlorophenol, Dibromol and salts thereof, cationic surfactants,including quaternaryammonium cations such as benzalkonium chloride,cetyl trimethylammonium bromide orchloride, didecyldimethylammoniumchloride, cetylpyridinium chloride, benzethonium chloride and others,and non-quaternary compounds, such as chlorhexidine, glucoprotamine,octenidine dihydrochloride etc.); strong oxidizers, such as ozone andpermanganate solutions; heavy metals and their salts, such as colloidalsilver, silver nitrate, mercury chloride, phenylmercury salts, copper,copper sulfate, copper oxide-chloride and the like, and strong acids(phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic acids) andalkalis (sodium, potassium, calcium hydroxides). However, many of thesecompounds are harmful to mammalian tissue. Moreover, these compoundsonly have a short-term effect resulting in a need to be reappliedconstantly.

Antibiotics can be administered to stop infection in individuals.However, such administration is not always effective. Numerous medicalapplications, including orthopedic, trauma, spine and general surgeryapplications, where the potential for infection is a serious concern,are not amenable to simple application of antiseptic or treatment withantibiotics. For example, infection can be a devastating complication ofa total joint arthroplasty (TJA). While some infections may be treatedby antibiotic suppression alone, more aggressive therapies, such astwo-stage re-implantation, are often required. The treatment ofpost-arthroplasty infections in 1999 cost over $200 million in the USalone. Spangehl, M. J., et al., J Bone Joint Surg. Am., 1999, 81(5),672-682. TJA infections occur when bacteria colonize the surface of theimplant. These species then form a resistant biofilm on the implantsurface, which nullifies the body's normal antibody response.

External fixation devices provide temporary but necessary rigidconstraints to facilitate bone healing. However, patients risk pin-tractinfection at the site extending from the skin-pin interface to withinthe bone tissue. Such complications can result in sepsis andosteomyelitis, which could require sequestrectomy for correction. Eventhe most stringent pin-handling and post-procedure protocols have only alimited effect. Studies have shown that such protocols do not reduce thechance of infection. Davies, R., et al. J Bone Joint Surg. Br., 2005,87-B, 716-719.

In minimally-invasive spine fusions, pedicle screws are first implantedin the bone of the vertebrae, and then rods are fixed into the heads ofthe screws to immobilize and stabilize the affected segments. Screws androds pass through the patient's skin into the spine space via acannulated channel. As in external fixation, screws and rods are alsoprone to pin-tract infections; due to the implants' pathway through theskin, the chance of contacting and/or passing harmful bacteria isgreatly increased.

Catheters and shunts are placed in any number of body cavities andvessels to facilitate the injection, drainage, or exchange of fluids.Infections are common in catheter placements and are largely dependenton how long the patient is catheterized. For example, Kass reports aninfection rate of virtually 100% for patients with indwelling urethralcatheters draining into an open system for longer than 4 days. Kass, E.H., Trans. Assoc. Am. Physicians, 1956, 69, 56-63.

Therefore, there is a need for substrates and materials withanti-infective surfaces, such as medical devices including implants,screws, rods, pins, catheters, stents, surgical tools and the like whichcould prevent infections by proactively killing bacteria that attempt tocolonize the device surface both pre- and post-operatively. Moreover,there is a need for anti-infective surfaces that may be employed inlocations particularly susceptible to hosting infectious agents, such aspublic places, common areas of buildings, fixtures and the like.

SUMMARY OF THE INVENTION

In some embodiments of the invention, a surface of interest isfunctionalized in accordance with a suitable functionalization methodand an anti-infective agent is disposed on the functionalized surface.

In some embodiments, the invention is directed to a compositioncomprising a substrate comprising a functionalized surface and aquaternary phosphonium compound covalently bound directly to thefunctionalized surface.

In some embodiments the surface of the substrate is functionalized witha functionalizing agent. In other embodiments the surface of thesubstrate may be natively functionalized.

In some embodiments a linker, having a proximal and a distal end, may becovalently bound on its proximal end to the functionalized surface ofthe substrate, and may be covalently bound on its distal end to aquaternary phosphonium compound.

In some embodiments a plurality of linkers may be covalently bound ontheir proximal ends to the functionalized surface or to a plurality offunctionalizing agents, with each linker being covalently bound on theirdistal end to a plurality of anti-infective agents. In some embodiments,the anti-infective agents may be all the same, for example, quaternaryphosphonium compounds. In other embodiments, the anti-infective agentsmay vary, for example, various quaternary phosphonium compounds, or acombination of quaternary phosphonium compounds with otheranti-infective agents. In some embodiments, the plurality offunctionalizing agents is independently identical or different. In someembodiments, the plurality of linkers is independently identical ordifferent.

In some embodiments, the composition may take a form of an antibacterialpolymer brush comprising a surface and a thickness. In some embodiments,varying antibacterial polymer brush thickness may have varyingantibacterial efficacy. In some embodiments, the antibacterial polymerbrush disrupts bacterial cells, thereby maintaining antibacterialactivity for prolonged duration without being reapplied.

In some embodiments, the anti-infective agent may be a quaternaryphosphonium compound having the radical formula of formula I:

wherein X₁, X₂, X₃, and X₄ are independently non-existent orindependently selected from O, S, NR₅, ═N—, PR₆, and ═P—, and whereinR₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from the groupconsisting of hydrogen, alkyls, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl,substituted cycloalkenyl, alkynyl, substituted alkynyl, haloalkyl,hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, haloalkoxy, aryl,substituted aryl, aryloxy, aralkyloxy, heteroaryl, substitutedheteroaryl, heterocycle, substituted heterocycle, amino, alkylamino,dialkylamino, hydroxyalkylamino, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl), carboxamido, (carboxamido)alkyl,methacrylate, methacrylamide, sulfonamide, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, mercaptoalkyl, carboxy, carboxyalkyl,ureido, guanidine, (heterocyclo)alkyl, (heteroaryl)alkyl.

In some embodiments, one of R₁, R₂, R₃, or R₄ may bind the quaternaryphosphonium compound either directly to the functionalized surface,functionalizing agent, or to the distal end of a linker. In otherembodiments, more than one of R₁, R₂, R₃, or R₄ may bind the quaternaryphosphonium compound either directly to a functionalized surface, to afunctionalizing agent, or to the distal end of a linker. In someembodiments, R₁, R₂, R₃ and R₄ may be the same. In other embodiments,some of R₁, R₂, R₃ and R₄ may be the same and some may be different.

Virtually any surface which may be functionalized is suitable for theinclusion of an anti-infective agent in accordance with the disclosedembodiments. Examples of such surfaces include but are not limited tometals, alloys, polymers, plastics, ceramics, silicon, glass,composites, tissue and surfaces with acidic protons.

Functionalization of substrates in accordance with the present inventionmay be achieved in a variety of ways. For example, the surfaces of thesubstrates can be functionalized by a reaction with functionalizingagents such as phosphonic acids, phosphoric acids, carboxylic acids,sulfonic acids, sulfinic acids, phosphonates, phosphonic acidanhydrides, phosphoric acid esters, phosphorus pentoxides, carboxylicacid esters, carboxylic anhydrides, sulfonates, sulfonic acidanhydrides, sulfinic esters, sulfinic anhydrides, alcohols, thiols,alkanes, alkenes, alkynes, and diazo compounds. In some embodiments, thesurfaces may be naturally functionalized.

Anti-infective agents as discussed herein may include bactericidal andbacteriostatic agents including disinfectants, antiseptics andantibiotics. Not all bactericidal and bacteriostatic agents may be usedas antiseptics on mammalian tissue as they may have adverse effectsthereon. Some embodiments of the present invention may involve useswithout contact of an anti-infective surface with mammalian tissue, suchas interior surfaces of plumbing fixtures, building materials, ductwork,clean rooms, etc. In such applications certain anti-infective agents maybe used, such as disinfectants, which would not be appropriate for usein applications in which contact with mammalian tissue was contemplatedor possible.

In other embodiments, the anti-infective composition of the presentinvention may involve contact with mammalian tissue and may comprisequaternary ammonium compounds such as choline and choline derivatives,quaternary ammonium dendrimers, silver, copper, and cationic species;silver and copper. In other embodiments anti-infective agents maycomprise quaternary phosphonium compounds such as phosphoniummethacrylate.

Devices made in accordance with the present disclosure provide amultitude of clinical benefits. For example, in partially externaldevices, anti-infective surfaces thereof may kill bacterial species atthe device-skin interface, thus preventing pin-site infections. Devicesincluding an anti-infective surface may prevent the colonization byinfectious species of implanted surfaces, potentially reducing theincidence of deep infection, especially in high-risk populations. Incatheters and shunts with anti-infective surfaces the potential forinfection is minimized by killing bacteria traveling up the intubatedpathway into the patient. Another example is in total hiparthroplasties; anti-infective hip stems may kill bacterial species andinhibit biofilm formation at the device-tissue interface, preventing thebacterial colonization of the hip replacement, which can lead toloosening due to infection and could require cost and painful hiprevision surgery. The anti-infective agent is highly stable underphysiological conditions. The anti-infective agent does not leach fromits material host, so there is no undesirable secondary result. Due toits nanometer scale, the anti-infective agent does not interfere withdesired mechanical surface features that may be critical to the functionof device such as an implant. The anti-infective agent is not visible tothe naked eye and does not obscure identifying features or productmarkings.

Devices in accordance with the present disclosure are not limited tomedical devices. For example, devices embodying the present disclosuresmay include fixtures, structures, fittings, barriers, and the likehaving anti-infective surfaces.

In some embodiments, the invention is directed to a method of making ananti-infective composition, the method comprising covalently binding ananti-infective agent to a functionalized surface of a substrate.

In some embodiments, the method comprises covalently binding aquaternary phosphonium compound either directly to a functionalizedsurface, to a functionalizing agent, or to a distal end of a linkerwhich is covalently bonded to the functionalized surface or to afunctionalizing agent.

In some embodiments, a linker is initially covalently bound on itsproximal end to a functionalized surface and an anti-infective agent,such as a quaternary phosphonium compound, is subsequently covalentlybound to the linker's distal end. In other embodiments, a linker isinitially covalently bound on its distal end to an anti-infective agent,such as a quaternary ammonium compound, and is subsequently covalentlybound on its proximal end to the functionalized surface.

In some embodiments, the anti-infective agent, e.g. quaternaryphosphonium compound, may be activated before covalently binding it to afunctionalized surface, a functionalizing agent, or a linker's distalend. In some embodiments, the functionalized surface may be activatedbefore covalently binding it to a linker's proximal end or to ananti-infective agent.

In some embodiments, the covalent binding may be performed throughsurface initiated atom transfer radical polymerization.

In some embodiments, after the linker is covalently bound on one of itsends, either on the proximal end to the functionalized surface or on thedistal end to the anti-infective agent, it is polymerized pursuant topredetermined parameters, such as time and amount of monomer, therebyobtaining a polymer brush structure with a desired surface andthickness. In some embodiments, after polymerization of the linker iscomplete, the unbound end of the linker (either distal or proximal) iscovalently bound to either the functionalized surface or theanti-infective agent. In some embodiments, varying polymer brushthickness may result in varying antimicrobial activity.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other features of the present disclosure, their nature,and various advantages will become more apparent upon consideration ofthe following detailed description, taken in conjunction with theaccompanying drawings, in which:

FIG. 1 depicts a schematic of an anti-infective agent bound to a surfacein accordance with at least one embodiment of the present disclosure.

FIG. 2 depicts a flow chart illustrating a method of preparing ananti-infective composition according to an embodiment of the invention.

FIG. 3 depicts a flow chart illustrating a method of preparing ananti-infective composition according to another embodiment of theinvention.

FIG. 4 depicts a scheme illustrating a method of preparing a particularanti-infective composition pursuant to example 1.

FIG. 5 depicts the anti-bacterial efficacy of two anti-infectivecompositions prepared pursuant to some embodiments of the inventionimmediately after the compositions were prepared (t=0).

FIG. 6 depicts the anti-bacterial efficacy of two anti-infectivecompositions prepared pursuant to some embodiments of the invention oneyear after the compositions were prepared (t=1 year).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purpose of the present disclosure, the term “alkyl” as used byitself or as part of another group refers to a linear or branched chainaliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C₁₋₁₂alkyl) or the number of carbon atoms designated (i.e., a C₁ alkyl suchas methyl, a C₂ alkyl such as ethyl, a C₃ alkyl such as propyl orisopropyl, etc.). In one embodiment, the alkyl group is chosen from alinear chain C₁₋₁₀ alkyl group. In another embodiment, the alkyl groupis chosen from a branched chain C₁₋₁₀ alkyl group. In anotherembodiment, the alkyl group is chosen from a linear chain C₁₋₆ alkylgroup. In another embodiment, the alkyl group is chosen from a branchedchain C₁₋₆ alkyl group. In another embodiment, the alkyl group is chosenfrom a linear chain C₁₋₄ alkyl group. In another embodiment, the alkylgroup is chosen from a branched chain C₁₋₄ alkyl group. In anotherembodiment, the alkyl group is chosen from a linear or branched chainC₂₋₄ alkyl group. Non-limiting exemplary C₁₋₁₀ alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl,iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.Non-limiting exemplary C₁₋₄ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkyl” as used by itself or as part of another group meansthat the alkyl as defined above is either unsubstituted or substitutedwith one, two, or three substituents independently chosen from nitro,haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, cycloalkyl, and the like. In one embodiment, theoptionally substituted alkyl is substituted with two substituents. Inanother embodiment, the optionally substituted alkyl is substituted withone substituent. Non-limiting exemplary optionally substituted alkylgroups include —CH₂CH₂NO₂, —CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh,—CH₂C₆H₁₁, and the like.

For the purpose of the present disclosure, the term “cycloalkyl” as usedby itself or as part of another group refers to saturated and partiallyunsaturated (containing one or two double bonds) cyclic aliphatichydrocarbons containing one to three rings having from three to twelvecarbon atoms (i.e., C₃₋₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl group has two rings. Inone embodiment, the cycloalkyl group has one ring. In anotherembodiment, the cycloalkyl group is chosen from a C₃₋₈ cycloalkyl group.In another embodiment, the cycloalkyl group is chosen from a C₃₋₆cycloalkyl group. Non-limiting exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and the like.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkyl” as used by itself or as part of another groupmeans that the cycloalkyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted cycloalkyl is substituted with two substituents.In another embodiment, the optionally substituted cycloalkyl issubstituted with one substituent. Non-limiting exemplary optionallysubstituted cycloalkyl groups include:

For the purpose of the present disclosure, the term “cycloalkenyl” asused by itself or part of another group refers to a partiallyunsaturated cycloalkyl group as defined above. In one embodiment, thecycloalkenyl has one carbon-to-carbon double bond. In anotherembodiment, the cycloalkenyl group is chosen from a C₄₋₈ cycloalkenylgroup. Exemplary cycloalkenyl groups include cyclopentenyl,cyclohexenyl, and the like.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkenyl” as used by itself or as part of another groupmeans that the cycloalkenyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkenyl is substituted with two substituents. In anotherembodiment, the optionally substituted cycloalkenyl is substituted withone substituent. In another embodiment, the cycloalkenyl isunsubstituted.

For the purpose of the present disclosure, the term “alkenyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one, two or three carbon-to-carbon double bonds. In oneembodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group. Inanother embodiment, the alkenyl group is chosen from a C₂₋₄ alkenylgroup. Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkenyl” as used herein by itself or as part of anothergroup means the alkenyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one to three carbon-to-carbon triple bonds. In oneembodiment, the alkynyl has one carbon-to-carbon triple bond. In oneembodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. Inanother embodiment, the alkynyl group is chosen from a C₂₋₄ alkynylgroup. Non-limiting exemplary alkynyl groups include ethynyl, propynyl,butynyl, 2-butynyl, pentynyl, and hexynyl groups.

For the purpose of the present disclosure, the term “optionallysubstituted alkynyl” as used herein by itself or as part of anothergroup means the alkynyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as usedby itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine, chlorine, bromine and/or iodineatoms. In one embodiment, the alkyl group is substituted by one, two, orthree fluorine and/or chlorine atoms. In another embodiment, thehaloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limitingexemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups.

For the purpose of the present disclosure, the term “hydroxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more, e.g., one, two, or three, hydroxy groups.In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group,i.e., substituted with one hydroxy group. In another embodiment, thehydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with twohydroxy groups. In another embodiment, the hydroxyalkyl group is chosenfrom a C₁₋₄ hydroxyalkyl group. Non-limiting exemplary hydroxyalkylgroups include hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl,1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl,4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

For the purpose of the present disclosure, the term “alkoxy” as used byitself or as part of another group refers to an optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedalkenyl, optionally substituted cycloalkenyl, optionally substitutedalkynyl or optionally substituted alkynyl attached to a terminal oxygenatom. In one embodiment, the alkoxy group is chosen from a C₁₋₄ alkoxygroup. In another embodiment, the alkoxy group is chosen from a C₁₋₄alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

For the purpose of the present disclosure, the term “alkoxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an alkoxy group. Non-limiting exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl.

For the purpose of the present disclosure, the term “heteroalkyl” asused by itself or part of another group refers to a stable linear orbranched chain hydrocarbon radical containing 1 to 10 carbon atoms andat least two heteroatoms, which can be the same or different, selectedfrom O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) canoptionally be oxidized; and/or 2) the nitrogen atom(s) can optionally bequaternized. The heteroatoms can be placed at any interior position ofthe heteroalkyl group or at a position at which the heteroalkyl group isattached to the remainder of the molecule. In one embodiment, theheteroalkyl group contains two oxygen atoms. Non-limiting exemplaryheteroalkyl groups include —CH₂OCH₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃,—CH₂NHCH₂CH₂OCH₂, —OCH₂CH₂NH₂, and —NHCH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term “haloalkoxy” as usedby itself or as part of another group refers to a haloalkyl attached toa terminal oxygen atom. Non-limiting exemplary haloalkoxy groups includefluoromethoxy, difluoromethoxy, trifluoromethoxy, and2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “aryl” as used byitself or as part of another group refers to a monocyclic or bicyclicaromatic ring system having from six to fourteen carbon atoms (i.e.,C₆₋₁₄ aryl). Non-limiting exemplary aryl groups include phenyl(abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In oneembodiment, the aryl group is chosen from phenyl or naphthyl.

For the purpose of the present disclosure, the term “optionallysubstituted aryl” as used herein by itself or as part of another groupmeans that the aryl as defined above is either unsubstituted orsubstituted with one to five substituents independently chosen fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, theoptionally substituted aryl is an optionally substituted phenyl. In oneembodiment, the optionally substituted phenyl has four substituents. Inanother embodiment, the optionally substituted phenyl has threesubstituents. In another embodiment, the optionally substituted phenylhas two substituents. In another embodiment, the optionally substitutedphenyl has one substituent. Non-limiting exemplary substituted arylgroups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl,4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl,2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl,3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The termoptionally substituted aryl is meant to include groups having fusedoptionally substituted cycloalkyl and fused optionally substitutedheterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “aryloxy” as used byitself or as part of another group refers to an optionally substitutedaryl attached to a terminal oxygen atom. A non-limiting exemplaryaryloxy group is PhO—.

For the purpose of the present disclosure, the term “aralkyloxy” as usedby itself or as part of another group refers to an aralkyl groupattached to a terminal oxygen atom. A non-limiting exemplary aralkyloxygroup is PhCH₂O—.

For the purpose of the present disclosure, the term “heteroaryl” or“heteroaromatic” refers to monocyclic and bicyclic aromatic ring systemshaving 5 to 14 ring atoms (i.e., C₅₋₁₄ heteroaryl) and 1, 2, 3, or 4heteroatoms independently chosen from oxygen, nitrogen and sulfur. Inone embodiment, the heteroaryl has three heteroatoms. In anotherembodiment, the heteroaryl has two heteroatoms. In another embodiment,the heteroaryl has one heteroatom. In one embodiment, the heteroaryl isa C₅ heteroaryl. In another embodiment, the heteroaryl is a C₆heteroaryl. Non-limiting exemplary heteroaryl groups include thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl,pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,3-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl,furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosenfrom thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl(e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-5-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl),isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, andisothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, andoxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl). The term “heteroaryl” is also meant to include possibleN-oxides. Exemplary N-oxides include pyridyl N-oxide, and the like.

For the purpose of the present disclosure, the term “optionallysubstituted heteroaryl” as used by itself or as part of another groupmeans that the heteroaryl as defined above is either unsubstituted orsubstituted with one to four substituents, e.g., one or twosubstituents, independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedheteroaryl has one substituent. In one embodiment, the optionallysubstituted is an optionally substituted pyridyl, i.e., 2-, 3-, or4-pyridyl. Any available carbon or nitrogen atom can be substituted. Inanother embodiment, the optionally substituted heteroaryl is anoptionally substituted indole.

For the purpose of the present disclosure, the term “heterocycle” or“heterocyclo” as used by itself or as part of another group refers tosaturated and partially unsaturated (e.g., containing one or two doublebonds) cyclic groups containing one, two, or three rings having fromthree to fourteen ring members (i.e., a 3- to 14-membered heterocyclo)and at least one heteroatom. Each heteroatom is independently selectedfrom the group consisting of oxygen, sulfur, including sulfoxide andsulfone, and/or nitrogen atoms, which can be quaternized. The term“heterocyclo” is meant to include cyclic ureido groups such as2-imidazolidinone and cyclic amide groups such as ρ3-lactam, γ-lactam,δ-lactam and ε-lactam. The term “heterocyclo” is also meant to includegroups having fused optionally substituted aryl groups, e.g., indolinyl.In one embodiment, the heterocyclo group is chosen from a 5- or6-membered cyclic group containing one ring and one or two oxygen and/ornitrogen atoms. The heterocyclo can be optionally linked to the rest ofthe molecule through a carbon or nitrogen atom. Non-limiting exemplaryheterocyclo groups include 2-imidazolidinone, piperidinyl, morpholinyl,piperazinyl, pyrrolidinyl, and indolinyl.

For the purpose of the present disclosure, the term “optionallysubstituted heterocyclo” as used herein by itself or part of anothergroup means the heterocyclo as defined above is either unsubstituted orsubstituted with one to four substituents independently selected fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, (heteroaryl)alkyl, and the like. Substitution mayoccur on any available carbon or nitrogen atom, and may form aspirocycle. Non-limiting exemplary optionally substituted heterocyclogroups include:

For the purpose of the present disclosure, the term “amino” as used byitself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as usedby itself or as part of another group refers to —NHR¹⁵, wherein R¹⁵ isalkyl.

For the purpose of the present disclosure, the term “dialkylamino” asused by itself or as part of another group refers to —NR^(16a)R^(16b),wherein R^(16a) and R^(16b) are each independently alkyl or R^(16a) andR^(16b) are taken together to form a 3- to 8-membered optionallysubstituted heterocyclo.

For the purpose of the present disclosure, the term “hydroxyalkylamino”as used by itself or as part of another group refers to —NHR¹⁷, whereinR¹⁷ is hydroxyalkyl.

For the purpose of the present disclosure, the term “(amino)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an amino group. Non-limiting exemplary amino alkylgroups include —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, and thelike.

For the purpose of the present disclosure, the term “(alkylamino)alkyl”as used by itself or as part of another group refers alkyl groupsubstituted an alkylamino group. A non-limiting exemplary(alkylamino)alkyl group is —CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term“(dialkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a dialkylamino group. Anon-limiting exemplary (dialkylamino)alkyl group is —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term “(cyano)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more cyano, e.g., —CN, groups. Non-limitingexemplary (cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term “carboxamido” asused by itself or as part of another group refers to a radical offormula —C(═O)NR^(24a)R^(24b), wherein R^(24a) and R^(24b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R^(24a) andR^(24b) taken together with the nitrogen to which they are attached froma 3- to 8-membered heterocyclo group. In one embodiment, R^(24a) andR^(24b) are each independently hydrogen or optionally substituted alkyl.Non-limiting exemplary carboxamido groups include —CONH₂, —CON(H)CH₃,—CON(CH₃)₂, and —CON(H)Ph.

For the purpose of the present disclosure, the term “(carboxamido)alkyl”as used by itself or as part of another group refers to an alkyl groupwith a carboxamido group. Non-limiting exemplary (carboxamido)alkylgroups include —CH₂CONH₂, —C(H)CH₃—CONH₂, and —CH₂CON(H)CH₃.

For the purpose of the present disclosure, the term “methacrylate” asused by itself or as part of another group refers to the radical offormula

wherein R²⁸ is independently hydrogen, or alkyl, or substituted alkyl,or cycloalkyl, or substituted cycloalkyl, cycloalkenyl, or substitutedcycloalkenyl, or alkenyl, or substituted cycloalkenyl, or alkynyl,substituted alkynyl, or haloalkyl, or hydroxyalkyl, or alkoxy, oralkoxyalkyl, or heteroalkyl, or haloalkoxy, or aryl, or substitutedaryl, or aryloxy, or aralkyloxy, or heteroaryl, or substitutedheteroaryl, or heterocycle, or substituted heterocycle, or amino, oralkylamino, or dialkylamino, or hydroxyalkylamino, or (amino)alkyl, or(alkylamino)alkyl, or (dialkylamino)alkyl, or (cyano)alkyl), orcarboxamido, or (carboxamido)alkyl, or sulfonamide, or alkylcarbonyl, orarylcarbonyl, or alkylsulfonyl, or arylsulfonyl, or mercaptoalkyl, orcarboxy, or carboxyalkyl, or ureido, or guanidine, or(heterocyclo)alkyl, or (heteroaryl)alkyl.

For the purpose of the present disclosure, the term “methacrylamide” asused by itself or as part of another group refers to the radical offormula

wherein R^(27a) and R^(27b) are independently hydrogen, or alkyl, orsubstituted alkyl, or cycloalkyl, or substituted cycloalkyl,cycloalkenyl, or substituted cycloalkenyl, or alkenyl, or substitutedcycloalkenyl, or alkynyl, substituted alkynyl, or haloalkyl, orhydroxyalkyl, or alkoxy, or alkoxyalkyl, or heteroalkyl, or haloalkoxy,or aryl, or substituted aryl, or aryloxy, or aralkyloxy, or heteroaryl,or substituted heteroaryl, or heterocycle, or substituted heterocycle,or amino, or alkylamino, or dialkylamino, or hydroxyalkylamino, or(amino)alkyl, or (alkylamino)alkyl, or (dialkylamino)alkyl, or(cyano)alkyl), or carboxamido, or (carboxamido)alkyl, or sulfonamide, oralkylcarbonyl, or arylcarbonyl, or alkylsulfonyl, or arylsulfonyl, ormercaptoalkyl, or carboxy, or carboxyalkyl, or ureido, or guanidine, or(heterocyclo)alkyl, or (heteroaryl)alkyl.

For the purpose of the present disclosure, the term “sulfonamido” asused by itself or as part of another group refers to a radical of theformula —SO₂NR^(23a)R^(23b), wherein R^(23a) and R^(23b) are eachindependently hydrogen, optionally substituted alkyl, or optionallysubstituted aryl, or R^(23a) and R^(23b) taken together with thenitrogen to which they are attached from a 3- to 8-membered heterocyclogroup. Non-limiting exemplary sulfonamido groups include —SO₂NH₂,—SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplaryalkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an optionally substituted aryl group. Anon-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfonyl groupis —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted aryl groups. A non-limiting exemplary arylsulfonyl group is—SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted by a —SH group.

For the purpose of the present disclosure, the term “carboxy” as used byitself or as part of another group refers to a radical of the formula—COOH.

For the purpose of the present disclosure, the term “carboxyalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted with a —COOH. A non-limitingexemplary carboxyalkyl group is —CH₂CO₂H.

For the purpose of the present disclosure, the term “aralkyl” as used byitself or as part of another group refers to an alkyl group substitutedwith one, two, or three optionally substituted aryl groups. In oneembodiment, the aralkyl group is a C₁₋₄ alkyl substituted with oneoptionally substituted aryl group. Non-limiting exemplary aralkyl groupsinclude benzyl, phenethyl, —CHPh₂, and —CH(4-FPh)₂.

For the purpose of the present disclosure, the term “ureido” as used byitself or as part of another group refers to a radical of the formula—NR^(22a)C(═O)NR^(22b)R^(22c), wherein R^(22a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(22b) and R^(22c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(22b) and R^(22c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NHC(C═O)NH₂ and —NHC(C═O)NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as usedby itself or as part of another group refers to a radical of the formula—NR^(25a)C(═NR²⁶)NR^(25b)R^(25c), wherein R^(25a), R^(25b) and R^(25c)are each independently hydrogen, alkyl, or optionally substituted aryl,and R²⁶ is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl,carboxamido, or sulfonamido. Non-limiting exemplary guanidino groupsinclude —NHC(C═NH)NH₂, —NHC(C═NCN)NH₂, —NHC(C═NH)NHCH₃, and the like.

For the purpose of the present disclosure, the term “(heterocyclo)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heterocyclogroups. In one embodiment, the (heterocyclo)alkyl is a (C₁₋₄)alkylsubstituted with one optionally substituted heterocyclo group.Non-limiting exemplary (heterocyclo)alkyl groups include:

For the purpose of the present disclosure, the term “(heteroaryl)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heteroarylgroups. In one embodiment, the (heteroaryl)alkyl group is a (C₁₋₄)alkylsubstituted with one optionally substituted heteroaryl group.Non-limiting exemplary (heteroaryl)alkyl groups include:

The present disclosure encompasses any of the compounds disclosed hereinwhich are isotopically-labelled (i.e., radiolabeled) by having one ormore atoms replaced by an atom having a different atomic mass or massnumber. Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and¹⁴C. Isotopically-labeled compounds can be prepared by methods known inthe art.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present disclosure is meant toencompass the use of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers canbe separated according to methods known in the art in view of thepresent disclosure. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that they include both E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent disclosure as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

The term “distal,” as used herein refers to the direction of thesubstrate's surface.

The term “proximal,” as used herein refers to the direction of theanti-infective agent.

The term “independently,” as used herein in connection with a radical, amolecule, an atom, or any other use is not dependent from anything else.Non-limiting examples is “X₁, X₂, X₃, and X₄ are independentlynon-existent or independently selected from,” meaning that X₁ can exist,not exist, or be selected from any of the molecules listed, regardlessof whether either of X₂, X₃, and X₄ exist, do not exist, or selectedfrom any of the molecules listed, regardless of whether X₁, X₂, X₃, andX₄ may be all the same, whether X₁, X₂, X₃, and X₄ may all vary, orwhether some of X₁, X₂, X₃, and X₄ may be the same and some may vary.

The term “radical,” as used herein refers to the molecule presentedabsent a hydrogen, thereby making the molecule available to covalentlybind to another molecule, for example to form a brush polymer (in whichthe molecule structure represents the monomer unit for the brushpolymer).

In general, in one or more embodiments, the invention is directed to acomposition comprising a functionalized surface of a substrate which iscovalently bound to a durable anti-infective agent, such as a quaternaryphosphonium compound. In other embodiments, the invention is directed tomethods of preparing an anti-infective composition by attaching adurable anti-infective agent, such as a quaternary phosphonium compoundto a functionalized surface.

Anti-Infective Composition

Now referring to FIG. 1, substrate's surface 10, in accordance with thepresent disclosure, is functionalized with a functionalizing layer 20,either natively occurring on the surface or obtained through afunctionalizing agent, and an anti-infective agent 30.

Substrates in accordance with the present invention include but are notlimited to any device(s) specific to an application by an orthopedic,cardiovascular, plastic, dermatologic, general, maxillofacial or neurosurgeon or physician including, but not limited to, cardiovascular orvascular implant device such as stents, replacement heart valves,replacement heart valve components, leaflets, sewing cuffs, orifices,annuloplasty rings, pacemakers, pacemaker polymer mesh bags, pacemakerleads, pacing wires, intracardiac patches/pledgets, vascular patches,vascular grafts, intravascular catheters, and defibrillators; tissuescaffolds; non-woven meshes, woven meshes, and foams; orthopedic implantdevices including orthopedic trauma implants, joint implants, spinalimplants, plates, screws, rods, plugs, cages, pins, nails, wires,cables, anchors, scaffolds, artificial joints selected from hand joints,wrist joints, elbow joints, shoulder joints, spine joints, hip joints,knee joints and ankle joints; bone replacement, bone fixation cerclageand dental and maxillofacial implants; spine implant devices includingintervertebral cages, pedicle screws, rods, connectors, cross-links,cables, spacers, facet replacement devices, facet augmentation devices,interspinous process decompression devices, interspinous spacers,vertebral augmentation devices, wires, plates, spine arthroplastydevices, facet fixation devices, bone anchors, soft tissue anchors,hooks, spacing cages, and cement restricting cages; diagnostic implants,biosensors, glucose monitoring devices, external fixation devices,external fixation implants, dental implants, maxillofacial implants,external facial fracture fixation devices and implants, contact lenses,intraocular implants, keratoprostheses; neurosurgical devices andimplants selected from shunts and coils; general surgical devices andimplants selected from drainage catheters, shunts, tapes, meshes, ropes,cables, wires, sutures, skin and tissue staples, bone anchors, softtissue anchors, bum sheets, and vascular patches; andtemporary/non-permanent implants. Specifically, such devices include ananti-infective agent to counter infective agents.

Surface 10 may be virtually any material which is amenable to eitherbeing natively functionalized or to reacting with a functionalizingagent to form a functionalizing layer 20. Examples of such materialsinclude metals, alloys, polymers, plastics, ceramics, silicon, glass,composites, tissue and surfaces with acidic protons, such as —OH or —NHgroups.

Metal surfaces which may be employed include titanium and its alloys,stainless steels, cobalt chrome alloys, aluminum, nickel, molybdenum,tantalum, zirconium, hafnium, vanadium, tin, magnesium, manganese,niobium, and alloys containing them; and the like.

Polymer surfaces which may be employed include but not limited tosynthetic and/or natural polymer molecules such as: polyamides,polyurethanes, polyureas, polyesters, polyketones, polyimides,polysulfides, polysulfoxides, polysulfones, polythiophenes,polypyridines, polypyrrols, polyethers, polysiloxanes, polysaccharides,fluoropolymers, amides, imides, polypeptides, polyethylene, polystyrene,polypropylene, liquid crystal polymers, thermoplastics,bismalimidtriazine (BT) resins, benzocyclobutene polymers, AjinomotoBuildup Films (ABF), low Coefficient of Thermal Expansion (CTE) films ofglass and epoxies, aramides, polyfluoroolefins, epoxies, silicones orcomposites containing these polymers.

Functionalizing layer 20 may be any layer suitable for a particularapplication. In some embodiments, functionalization layer 20 may benative functionalization of the surface. In other embodiments,functionalization layer 20 may be obtained through a functionalizingagent or a plurality of functionalizing agents. In yet otherembodiments, functionalization layer 20 may be obtained through acombination of native functionalization and due to a functionalizingagent or a plurality of functionalizing agents. In some embodiments theplurality functionalizing agents may be all identical, all different, orsome identical and some different. Such functionalized surfaces can beused to covalently bond subsequent material, such as a linker, aplurality of linkers, layers of anti-infective agent or a plurality ofanti-infective agents.

Functionalization of substrate surfaces in accordance with the presentinvention may be achieved in a variety of ways. For example, it ispossible to functionalize the surface of a polymer with an oxide,alkoxide or mixed oxide-alkoxide layer using an alkoxide precursor. Inone embodiment, the polymer surface may be coated with a continuousoxide adhesion layer, i.e., a layer that is formed by a matrix ofindividual spread molecules that are chemically bonded and linked toeach other, as opposed to individual molecules sparsely covering thesurface. In this embodiment metal alkoxide molecules are bonded togetheron at least a portion of a polymer surface to form a continuous layerand then converted to an oxide functionalizing layer. In someembodiments, the functionalized surface is coated with a self assembledmonolayer (SAM) of functionalizing agent covalently bound to thefunctionalized surface.

It is further possible to form an adherent coating layer that may befurther functionalized with adherent species by heating a self-assembledlayer of a functionalized phosphonic acid on the native oxide surface ofa substrate. This process, described in detail in U.S. PatentApplication Publication 2004/0023048, the entirety of which isincorporated herein by reference, provides on the native oxide surfaceof a material a multi-segmented, phosphorous-based coating layer havinga difunctional organophosphonic acid-based segment bonded to the nativeoxide surface of the material and a linking segment bonded to theorganophosphonic acid-based segment. In accordance with this process, aphosphorous-based coating layer may be provided having a plurality offunctionalized organophosphonate moieties bonded to the native oxidesurface of a substrate by a phosphonate bond and a plurality of one ormore anti-infective coating moieties, each coating moiety being bondedto the functional group of at least one functionalized organophosphonatemoiety. When bonded by means of a metal complex, the metal complex isfurther characterized by being derived from a metal reagent, preferablya metal alkoxide reagent.

The surfaces of the substrates can be further functionalized by areaction with functionalizing agents such as phosphonic acids,phosphoric acids, carboxylic acids, sulfonic acids, sulfinic acids,phosphonates, phosphonic acid anhydrides, phosphoric acid esters,phosphorus pentoxides, carboxylic acid esters, carboxylic anhydrides,sulfonates, sulfonic acid anhydrides, sulfinic esters, sulfinicanhydrides, alcohols, thiols, alkanes, alkenes, alkynes, and diazocompounds. In some embodiments, a single functionalizing agent isreacted to functionalize the surface. In other embodiments, a pluralityof functionalizing agents are reacted to functionalize the surface.

It is yet further possible to covalently bond the anti-infective agentto a functionalizing agent before covalently bonding said functionalizedanti-infective agent to a natively functionalized surface, afunctionalizing agent bound to a surface, or a linker's distal end. Insome embodiments, it is possible to covalently bond a plurality ofanti-infective agents to a plurality of functionalizing agents beforecovalently bonding said plurality of anti-infective agents to a nativelyfunctionalized surface, plurality of functionalizing agents bound to thesurface, or a plurality of linker's distal ends. In some embodiments,the plurality of anti-infective agents (e.g. quaternary phosphoniumcompound) may be all identical, all different, or some identical andsome different.

Such functionalized surfaces can be used to covalently bond subsequentmaterial or layers thereof on the surface, which in the presentinvention includes anti-infective agents, or linkers bound toanti-infective agents. A plurality of one or more anti-infective agentsmay be covalently bonded to the functionalized surface, thefunctionalizing agents on the surface (which may vary), and the linkerscovalently bound to the surface (which may vary).

Anti-infective agents 30 that may be employed may include bactericidaland bacteriostatic agents including disinfectants, antiseptics andantibiotics. Disinfectants include active chlorine such ashypochlorites, chloramines, dichloroisocyanurate andtrichloroisocyanurate, wet chlorine, chlorine dioxide and the like,active oxygen, including peroxides, such as peracetic acid, potassiumpersulfate, sodium perborate, sodium percarbonate and urea perhydrate,iodine compounds such as iodpovidone, iodine tincture, iodinatednonionic surfactants, concentrated alcohols such as ethanol, n-propanoland isopropanol and mixtures thereof; 2-phenoxyethanol and 1- and2-phenoxypropanols, phenolic compounds, cresols, halogenated phenols,such as hexachlorophene, triclosan, trichlorophenol, tribromophenol,pentachlorophenol, Dibromol and salts thereof, cationic surfactants,including quaternary ammonium cations such as benzalkonium chloride,cetyl trimethylammonium bromide or chloride, didecyldimethylammoniumchloride, cetylpyridinium chloride, benzethonium chloride and others,and non-quaternary compounds, such as chlorhexidine, glucoprotamine,octenidine dihydrochloride etc.); strong oxidizers, such as ozone andpermanganate solutions; heavy metals and their salts, such as colloidalsilver, silver nitrate, mercury chloride, phenylmercury salts, copper,copper sulfate, copper oxide-chloride and the like, and strong acids(phosphoric, nitric, sulfuric, amidosulfuric, toluenesulfonic acids) andalkalis (sodium, potassium, calcium hydroxides).

Organic anti-infective moieties that may be added to a functionalizinglayer include quaternary ammonium alkylamines, quaternary ammoniumalkanols, usinic acid; cationic peptides such as cecropins neutrophildefensins, polyphemusin, gramicidins, thionins, histone-derivedcompounds, beta-hairpin, hemoglobin, lactoferrin; anionic peptides suchas neuropeptide precursors, aromatic dipeptides, hemocyanin derivatives;other antimicrobial peptides such as bacteriacins, cathelicidin,thrombocidin, and histanins; antibodies, antibiotics, includingtetracyclines, amphenicols, penicillins, cephalosporins, monobactams,carbapenems, sulfanomides, trimethoprim, macrolides, streptomycins,quinolones, glycopeptides, polymyxins, lincosamides, streptogramins,imidazole derivatives, nitrofuran derivatives; steroids; chlorhexidine;phenol compounds including triclosan; epoxides; polymers and/orpolypeptides which have anti-infective properties.

Inorganic anti-infective coating layers that may be bonded includesilver, copper, zinc oxides, titanium oxides, zeolites, silicates,calcium hydroxide, iodine, sodium hypochlorite, sulfites, and sulfates.

Other anti-infective moieties include, quaternary phosphonium compounds,such as Triethyl(12-(methacryloyloxy)dodecyl)phosphonium bromide,quaternary ammonium compounds, such as benzethonium chloride,cetrimonium bromide, cetrimonium chloride, dimethyldioctadecylammoniumchloride, tetramethylammonium hydroxide; quaternary ammonium alkyldendrimers, silver, copper, cationic species such as benzalkoniumchloride, Bronidox; and alkylated choline.

In some embodiments the anti-infective agent used is a quaternaryphosphonium compound comprising the radical of formula I:

wherein X₁, X₂, X₃, and X₄ are independently non-existent orindependently selected from O, S, NR₅, ═N—, PR₆, and ═P—; and whereinR₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from the groupconsisting of hydrogen, alkyls, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl,substituted cycloalkenyl, alkynyl, substituted alkynyl, haloalkyl,hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, haloalkoxy, aryl,substituted aryl, aryloxy, aralkyloxy, heteroaryl, substitutedheteroaryl, heterocycle, substituted heterocycle, amino, alkylamino,dialkylamino, hydroxyalkylamino, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl), carboxamido, (carboxamido)alkyl,methacrylate, methacrylamide, sulfonamide, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, mercaptoalkyl, carboxy, carboxyalkyl,ureido, guanidine, (heterocyclo)alkyl, (heteroaryl)alkyl.

In some embodiments, one of R₁, R₂, R₃, or R₄ may bind the quaternaryphosphonium compound either directly to the functionalized surface,functionalizing agent, or to the distal end of a linker. In otherembodiments, more than one of R₁, R₂, R₃, or R₄ may bind the quaternaryphosphonium compound either directly to a functionalized surface, to afunctionalizing agent, or to the distal end of a linker. In someembodiments, R₁, R₂, R₃ and R₄ may be the same. In other embodiments,some of R₁, R₂, R₃ and R₄ may be the same and some may be different.

In some embodiments, the anti-infective agent used is the radical of thefollowing structure or the monomer of the following structure:

wherein n2 is between 1 and 50.

In one embodiment, the anti-infective agent used is the radical of thefollowing structure or the monomer of the following structure:

In some embodiments, the anti-infective agent use is the radical of thefollowing structure or the monomer of the following structure:

wherein n3 is between 1 and 50.

In one embodiment, the anti-infective agent used is the radical of thefollowing structure or the monomer of the following structure:

Not all bactericidal and bacteriostatic agents may be used asantiseptics on mammalian tissue as they may have adverse effectsthereon. It will be apparent to those skilled in the art that someembodiments of the present invention may apply to uses that do notinvolve contact of an anti-infective surface with mammalian tissue, suchas the fabric used for surgical barriers and the interior surfaces ofplumbing fixtures, building materials, ductwork, clean rooms, etc. Insuch applications certain anti-infective agents may be used, such asdisinfectants, which would not be appropriate for use in applications inwhich contact with mammalian tissue would be contemplated or possible.

In some embodiments anti-infective agents used in applications whichinvolve possible contact with mammalian tissue include but are notlimited to quaternary phosphonium compounds such as phosphoniummethacrylate, quaternary ammonium compounds such as choline and cholinederivatives, quaternary ammonium dendrimers, silver, copper, andcationic species. Quaternary ammonium compounds (“quats”) with longalkyl chains show proven biocidal properties by disruption of cellwalls. Nakagawa, Y., et al., Appl. Environ. Microbial., 1984, 47:3,513-518, incorporated by reference herein in its entirety.

In certain embodiments, a linker, having a proximal end and a distalend, may be present between the anti-infective agent and thefunctionalized surface. In some embodiments, the linker may becovalently bound to the anti-infective agent on its distal end. In someembodiments, the linker may be covalently bound on its proximal end tothe functionalized surface, or a functionalizing agent.

In some embodiments, a plurality of linkers, each having a distal and aproximal end, may be covalently bound on their proximal end to aplurality of functionalizing agents or directly to a nativelyfunctionalized surface. In some embodiments, a second amount of theplurality of functionalizing agents may remain not bound to theplurality of linkers.

In some embodiments, a plurality of anti-infective agents (such as aquaternary phosphonium compound) may be covalently bound to a pluralityof linkers (which are either directly bound to the functionalizedsurface or are bound to a functionalizing agent). In some embodiments, asecond plurality of anti-infective agents (such as a quaternaryphosphonium compound) may be covalently bound to the second plurality offunctionalizing agents (which previously were not bound to a pluralityof linkers).

In certain embodiments, the plurality of linkers may be all identical,all different, or some identical and some different. In certainembodiments, the plurality of functionalizing agents may be allidentical, all different, or some identical and some different. Incertain embodiments, the plurality of anti-infective agents may be allidentical, all different, or some identical and some different.

In some embodiments, the linker may be a radical of the following:

Wherein n1 is between 1 and 100 and R′ is independently a hydrogen, oran anti-infective agent (such as a quaternary phosphonium compound).

In certain embodiments, the composition of the present invention has thestructure

wherein n1 is between 1 and 100.

In certain embodiments, the anti-infective material may be bound to thelinker's distal end or to the functionalized surface in a pattern or ina micropattern.

Method for Making an Anti-Infective Composition

Now referring to FIG. 2 illustrating a method 200 for making ananti-infective composition according to an embodiment of the invention.In one embodiment, the method comprises attaching an anti-infectiveagent, such as a quaternary phosphonium compound, to a functionalizedsurface, which is functionalized either natively or with afunctionalizing agent, in accordance with the methods describedhereinabove.

In some embodiments, attaching a quaternary phosphonium compound to afunctionalized surface comprises: introducing a functionalized surfacepursuant to block 202 (functionalized either natively or with afunctionalizing agent, in accordance with the methods describedhereinabove), optionally activating the functionalized surface (notshown), polymerizing a linker, having a proximal and a distal end, toform a covalent bond between the activated functionalized surface andthe proximal end of the linker pursuant to block 204, and subsequentlycovalently binding the distal end of the linker to the quaternaryphosphonium compound anti-infective agent (which may be functionalizedand/or activated) pursuant to block 206.

In other embodiments, as illustrated in FIG. 3 by method 300, the ordermay vary. For example, attaching a quaternary phosphonium compound to afunctionalized surface may comprise: polymerizing a linker, having aproximal and a distal end, to form a covalent bond between theanti-infective agent (e.g., quaternary phosphonium compound) and thedistal end of the linker pursuant to block 302, introducing afunctionalized surface pursuant to block 304 (functionalized eithernatively or with a functionalizing agent, in accordance with the methodsdescribed hereinabove), optionally activating the functionalized surface(not shown), and subsequently covalently binding the proximal end of thelinker to the functionalized surface pursuant to block 306.

In yet other embodiments, attaching a quaternary phosphonium compound toa functionalized surface may comprise: polymerizing a linker, having aproximal and a distal end, to form a covalent bond between thequaternary phosphonium compound and the distal end of the linker; andsimultaneously covalently binding the proximal end of the linker to thefunctionalized surface.

In some embodiments, covalently bonding the linker may comprise usingSurface-Initiated Atom Transfer Radical Polymerization (SI ATRP). Insome embodiments polymerizing through SI ATRP comprises: introducing ananti-infective agent (e.g., quaternary phosphonium compound),introducing an initiator (e.g., alkyl halide initiator), introducing atransition metal complex (e.g., CuBr), introducing a ligand (e.g.,N,N,N′,N″,N′″-pentamethyldiethylenetriamine), and polymerizing for apredetermined time to obtain a desired polymer brush thickness.

In some embodiments, the ratio of the components in the polymerizationstep is 2:1:1.4 of monomer:metalcomplex:ligand. In some embodiments, thepolymer brush thickness effects the antibacterial efficacy. In someembodiments, the composition disclosed herein shows greater than 99%reduction in a variety of bacteria for prolonged duration.

It is believed that one of ordinary skill in the art can, using thepreceding description and the following illustrative examples, make andutilize the compounds and articles of the present invention and practicethe claimed methods. The following examples are given to illustrate thepresent invention. It should be understood that the invention is not tobe limited to the specific conditions or details described in theseexamples.

Example 1: Synthesis of Antibacterial Polymer Brushes ViaSurface-Initiated Atom Transfer Radical Polymerization (SI-ATRP)

Referring to FIG. 4, glass bead-blasted Ti-alloy (Ti₆V_(a)Al) coupons 1were cleaned and contacted with phosphonoundecanol (PUL) in a 15 mMsolution of PUL in ethanol, thereby covalently binding the PUL to thetitanium alloy, and forming a Self Assembled Monolayer (SAM) of PUL onthe titanium alloy surface as illustrated by numeral 2. Step a is alsoreferred to, in some embodiments of the invention, as covalently bindinga functionalizing agent to the surface, where the functionalizing agentin this instance is PUL.

The terminal hydroxyl group of the functionalizing agents 2 (PUL) wereesterified with α-bromoisobutyryl bromide in dichloromethane to form thecomposition illustrated by numeral 3. Step b is also referred to, insome embodiments of the invention, as activating the surface, therebypreparing it for subsequent SI-ATRP of the linker (i.e. covalentlybinding the linker on its proximal end to the surface) and ultimately ofthe anti-infective (i.e. covalently binding the anti-infective agent tothe linker on its distal end).

The SI-ATRP of the anti-infective agent, quaternary phosphonium compoundphosphonium methaceylate illustrated by numeral 4, was performed inwater in the presence of CuBr and a ligandN,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDETA). The ratio employedwas [monomer]:[Cu]:[PMDETA]=2:1.0:1.4. However, one of ordinary skill inthe art will appreciate that the polymerization time and amount ofmonomer used may vary to control the thickness of the polymer brushesand the resulting antibacterial properties of polymer brush surfaces.Step c is also referred to, in some embodiments of the invention, aspolymerizing a linker onto the activated functionalized surface andcovalently binding the quaternary phosphonium compound to the linker.

FIG. 5 illustrates the prolonged antibacterial performance of thecomposition prepared according to embodiments of the invention. Acomposition comprising a radical of the quaternary phosphonium compoundof the following structure:

have shown a 99.5% killing of S. aureus and a 98% of E. coli.Additionally, a composition comprising a radical of the quaternaryphosphonium compound of the following structure:

have shown a 98.9% killing of S. aureus and a 99% of E. coli.

The antibacterial activity and efficacy was shown to be maintained evenafter aging the composition for one year as 6 illustrated in FIG. 6.Test coupons were placed in a modified ASTM E2149 efficacy study usingS. aureus (ATCC#29213) with an inoculum level of 10⁶Colony Forming Units(CFU) per ml. After a 24 hour exposure, the coupons were evaluatedrelative to untreated samples for CFU/ml reduction from bacteriarecovered directly from the sample surface, and showed >95% killing atthe surface for both treatments. Specifically, a 95.2% killing wasobserved at the titanium surface treated with the quaternaryorganophosphonate compound of the following structure:

No reduction in antibacterial efficacy was observed outside of themargin of error of the experiment. In changes in the antibacterialefficacy are likely due to variability in the treatment and the essayrather that real reduction in efficacy over time. Additionally, a 99.8%killing was observed at the titanium surface treated with the quaternaryorganophosphonate compound of the following structure:

Similarly to the previous compound, no reduction in antibacterialefficacy was observed outside of the margin of error of the experiment.In changes in the antibacterial efficacy are likely due to variabilityin the treatment and the essay rather that real reduction in efficacyover time.

Example 2: Synthesis of a Quaternary Phosphonium Compound PhosphoniumMethacrylate

A 100 mL pressure tube was charged successively with acetonitrile (18mL), triethylphosphine (2.05 mL, 17.3 mmol) and 12-bromo-1-dodecanol(4.00 g, 15.1 mmol). The mixture was heated at 90° C. for 2 days andconcentrated in vacuum. The residue was dissolved in dichloromethane (10mL). The solution was added drop-wise into ether (150 mL) with stirringto precipitate the product. After stirring for an additional one hour,the precipitates were collected by filtration, washed with ethanol, andair-dried to afford the target compound, i.e.Triethyl(12-hydroxydodecyl)phosphonium bromide (4.4 g, 65%).

To a solution of triethyl(12-hydroxydodecyl)phosphonium bromide (4.00 g,10.4 mmol) in chloroform (50 mL) was slowly added methacryloyl chloride(1.07 mL, 11.0 mmol) at 0° C. and the mixture was stirred at roomtemperature for three days. Upon completion, the mixture was dilutedwith dichloromethane. Sodium carbonate (5 g) was added to the mixture.After stirring for 30 min, the mixture was filtered and concentrated invacuum. The residual oil was then passed through a fritted glass filterto afford the product, i.e.Triethyl(12-(methacryloyloxy)dodecyl)phosphonium bromide (4.7 g,quantitative).

For simplicity of explanation, the embodiments of the methods of thisdisclosure are depicted and described as a series of acts. However, actsin accordance with this disclosure can occur in various orders and/orconcurrently, and with other acts not presented and described herein.Furthermore, not all illustrated acts may be required to implement themethods in accordance with the disclosed subject matter. In addition,those skilled in the art will understand and appreciate that the methodscould alternatively be represented as a series of interrelated statesvia a state diagram or events.

In the foregoing description, numerous specific details are set forth,such as specific materials, dimensions, processes parameters, etc., toprovide a thorough understanding of the present invention. Theparticular features, structures, materials, or characteristics may becombined in any suitable manner in one or more embodiments. The words“example” or “exemplary” are used herein to mean serving as an example,instance, or illustration. Any aspect or design described herein as“example” or “exemplary” is not necessarily to be construed as preferredor advantageous over other aspects or designs. Rather, use of the words“example” or “exemplary” is intended to present concepts in a concretefashion. As used in this application, the term “or” is intended to meanan inclusive “or” rather than an exclusive “or”. That is, unlessspecified otherwise, or clear from context, “X includes A or B” isintended to mean any of the natural inclusive permutations. That is, ifX includes A; X includes B; or X includes both A and B, then “X includesA or B” is satisfied under any of the foregoing instances. In addition,the articles “a” and “an” as used in this application and the appendedclaims should generally be construed to mean “one or more” unlessspecified otherwise or clear from context to be directed to a singularform. Reference throughout this specification to “an embodiment”,“certain embodiments”, or “one embodiment” means that a particularfeature, structure, or characteristic described in connection with theembodiment is included in at least one embodiment. Thus, the appearancesof the phrase “an embodiment”, “certain embodiments”, or “oneembodiment” in various places throughout this specification are notnecessarily all referring to the same embodiment.

Although certain presently preferred embodiments of the invention havebeen specifically described herein, it will be apparent to those skilledin the art to which the invention pertains that variations andmodifications of the various embodiments shown and described herein maybe made without departing from the spirit and scope of the invention.Accordingly, it is intended that the invention be limited only to theextent required by the appended claims and the applicable rules of law.All references cited herein are incorporated fully by reference.

What is claimed is:
 1. A composition comprising a substrate comprising afunctionalized surface; and a quaternary phosphonium compound bonded tothe functionalized surface, wherein the quaternary phosphonium compoundhas a radical of formula I

wherein X₁, X₂, X₃, and X₄ are independently non-existent orindependently selected from O, S, NR₅, ═N—, PR₆, and ═P—; and whereinR₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from the groupconsisting of hydrogen, alkyls, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl,substituted cycloalkenyl, alkynyl, substituted alkynyl, haloalkyl,hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, haloalkoxy, aryl,substituted aryl, aryloxy, aralkyloxy, heteroaryl, substitutedheteroaryl, heterocycle, substituted heterocycle, amino, alkylamino,dialkylamino, hydroxyalkylamino, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl), carboxamido, (carboxamido)alkyl,methacrylate, methacrylamide, sulfonamide, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, mercaptoalkyl, carboxy, carboxyalkyl,ureido, guanidine, (heterocyclo)alkyl, (heteroaryl)alkyl.
 2. Thecomposition of claim 1, wherein the functionalized surface is nativelyfunctionalized or functionalized with a functionalizing agent covalentlybonded thereto.
 3. The composition of claim 2, further comprising alinker, having a proximal end and a distal end, wherein the linker iscovalently bonded on its proximal end to the natively functionalizedsurface, and wherein the linker is covalently bonded on its distal endto the quaternary phosphonium compound.
 4. The composition of claim 2,further comprising a linker, having a proximal and a distal end, whereinthe linker is covalently bonded on its proximal end to thefunctionalizing agent, and wherein the linker is covalently bonded onits distal end to the quaternary phosphonium compound.
 5. Thecomposition of claim 1, wherein the functionalized surface is selectedfrom the group consisting of metals, alloys, polymers, plastics,ceramics, silicon, glass, composites, tissue and surfaces with acidicprotons.
 6. The composition of claim 2, wherein the functionalizedsurface is functionalized with a functionalizing agent selected from thegroup consisting of phosphonic acids, phosphoric acids, carboxylicacids, sulfonic acids, sulfinic acids, phosphonates, phosphonic acidanhydrides, phosphoric acid esters, phosphorus pentoxides, carboxylicacid esters, carboxylic anhydrides, sulfonates, sulfonic acidanhydrides, sulfinic esters, sulfinic anhydrides, alcohols, thiols,alkanes, alkenes, alkynes, and diazo compounds.
 7. The composition ofclaim 1, wherein the quaternary phosphonium compound has a structure

wherein n2 is between 1 and
 50. 8. The composition of claim 4, whereinthe linker has a structure

wherein n1 is between 1 and 100 and R′ is independently a hydrogen, or aquaternary phosphonium compound.
 9. The composition of claim 4 having astructure

wherein n1 is between 1 and
 100. 10. A method for preparing acomposition comprising attaching a quaternary phosphonium compound to afunctionalized surface of a substrate, wherein the quaternaryphosphonium compound has a radical of formula I

wherein X₁, X₂, X₃, and X₄ are independently non-existent orindependently selected from O, S, NR₅, ═N—, PR₆, and ═P—; and whereinR₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from the groupconsisting of hydrogen, alkyls, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl,substituted cycloalkenyl, alkynyl, substituted alkynyl, haloalkyl,hydroxyalkyl, alkoxy, alkoxyalkyl, heteroalkyl, haloalkoxy, aryl,substituted aryl, aryloxy, aralkyloxy, heteroaryl, substitutedheteroaryl, heterocycle, substituted heterocycle, amino, alkylamino,dialkylamino, hydroxyalkylamino, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl), carboxamido, (carboxamido)alkyl,methacrylate, methacrylamide, sulfonamide, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, mercaptoalkyl, carboxy, carboxyalkyl,ureido, guanidine, (heterocyclo)alkyl, and (heteroaryl)alkyl, and arelinked to the phosphorus through any one of oxygen, nitrogen, sulfur,carbon, and phosphorus.
 11. The method of claim 10, wherein attachingthe quaternary phosphonium compound to a functionalized surfacecomprises covalently bonding a functionalizing agent to the surface; andcovalently bonding the quaternary phosphonium compound to thefunctionalized surface.
 12. The method of claim 10, wherein attaching aquaternary phosphonium compound to a functionalized surface comprisescovalently binding a functionalizing agent to the surface; activatingthe surface; polymerizing a linker, having a proximal and a distal end,to form a covalent bond between the activated functionalized surface andthe proximal end of the linker; and subsequently covalently binding thedistal end of the linker to the quaternary phosphonium compound.
 13. Themethod of claim 10, wherein attaching a quaternary phosphonium compoundto a functionalized surface comprises polymerizing a linker, having aproximal and a distal end, to form a covalent bond between thequaternary phosphonium compound and the distal end of the linker; andsubsequently covalently binding the proximal end of the linker to thefunctionalized surface.
 14. The method of claim 10, wherein thefunctionalized surface is selected from the group consisting of metals,alloys, polymers, plastics, ceramics, silicon, glass, composites, tissueand surfaces with acidic protons.
 15. The method of claim 11, whereinthe functionalizing agent is selected from the group consisting ofphosphonic acids, phosphoric acids, carboxylic acids, sulfonic acids,sulfinic acids, phosphonates, phosphonic acid anhydrides, phosphoricacid esters, phosphorus pentoxides, carboxylic acid esters, carboxylicanhydrides, sulfonates, sulfonic acid anhydrides, sulfinic esters,sulfinic anhydrides, alcohols, thiols, alkanes, alkenes, alkynes, anddiazo compounds.
 16. The method of claim 10, wherein the quaternaryphosphonium compound is a radical of

wherein n2 is between 1 and
 50. 17. The method of claim 13, wherein thelinker has a structure

wherein n1 is between 1 and 100 and R′ is independently a hydrogen, or aquaternary phosphonium compound.
 18. The method of claim 12, wherein thecomposition has a structure

wherein n1 is between 1 and
 100. 19. The composition of claim 1, whereinthe quaternary phosphonium compound is a radical of

wherein n3 is between 1 and
 50. 20. The method of claim 10, wherein thequaternary phosphonium compound is a radical of

wherein n3 is between 1 and 50.